Therapeutic Inhibition of PHF21B Attenuates Pathological Cardiac Hypertrophy by Inhibiting the BMP4/GSK3β/β-Catenin Axis.

Abstract

Background: Pathological cardiac hypertrophy is a hallmark of various cardiovascular diseases, unfortunately, effective targeted therapies are still lacking. This study aims to verify the role of plant-homeodomain finger protein21b (PHF21B) in pathological cardiac hypertrophy.

Methods: Angiotensin-II (Ang II) induced cardiomyocyte hypertrophy in vitro, and short hairpin (sh) RNA-mediated PHF21B silencing was used to assess its role in hypertrophic growth. Transverse aortic constriction (TAC) was performed to induce cardiac hypertrophy in mice. To assess the effect of PHF21B on pathological cardiac hypertrophy in vivo, the myocardium was transduced with adeno-associated virus 9 (AAV9) encoding a PHF21B-targeting shRNA for gene ablation. Chromatin immunoprecipitation-polymerase chain reaction (PCR), western blotting, and quantitative reverse transcription-PCR were performed to elucidate the mechanisms through which PHF21B regulates pathological cardiac hypertrophy.

Results: This investigation revealed that PHF21B levels were elevated in patients with pathological cardiac hypertrophy. PHF21B inhibition alleviated pressure overload-induced cardiac dysfunction and hypertrophy in vivo, and Ang-II-induced cardiomyocyte hypertrophy in vitro. Genome-wide transcriptome analysis and biological experiments revealed that PHF21B silencing inhibited the Wnt signalling pathway, include the protein expression of β-catenin, and the phosphorylation of glycogen synthase kinase (GSK)-3β. Mechanistically, PHF21B influenced the translation of bone morphogenetic protein (BMP)-4 and facilitated the activation of the GSK3β/β-catenin pathway. The anti-hypertrophic effects of PHF21B knockdown were blocked by BMP4 supplementation.

Conclusions: Collectively, our results demonstrated that PHF21B is contributes to pathological cardiac hypertrophy by regulating BMP4 expression and the GSK3β/β-catenin pathway. The inhibition of PHF21B is a potential new therapeutic strategy to mitigate pathological cardiiac hypertrophy.